Rational Approach to Identify RNA Targets of Natural Products Enables Identification of Nocathiacin as an Inhibitor of an Oncogenic RNA.
ACS Chem Biol
; 17(2): 474-482, 2022 02 18.
Article
em En
| MEDLINE
| ID: mdl-35044149
ABSTRACT
The discovery of biofunctional natural products (NPs) has relied on the phenotypic screening of extracts and subsequent laborious work to dereplicate active NPs and define cellular targets. Herein, NPs present as crude extracts, partially purified fractions, and pure compounds were screened directly against molecular target libraries of RNA structural motifs in a library-versus-library fashion. We identified 21 hits with affinity for RNA, including one pure NP, nocathiacin I (NOC-I). The resultant data set of NOC-I-RNA fold interactions was mapped to the human transcriptome to define potential bioactive interactions. Interestingly, one of NOC-I's most preferred RNA folds is present in the nuclease processing site in the oncogenic, noncoding microRNA-18a, which NOC-I binds with low micromolar affinity. This affinity for the RNA translates into the selective inhibition of its nuclease processing in vitro and in prostate cancer cells, in which NOC-I also triggers apoptosis. In principle, adaptation of this combination of experimental and predictive approaches to dereplicate NPs from the other hits (extracts and partially purified fractions) could fundamentally transform the current paradigm and accelerate the discovery of NPs that bind RNA and their simultaneous correlation to biological targets.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
/
MicroRNAs
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos